D
eep-vein thrombosis (DVT) has an estimated annual in-cidence of 67 per 100 000 among the general popula-tions.1,2Despite adequate therapy, 1% to 8% of patientsin whom pulmonary embolism develops will die,3–5whereas
oth-ers will experience long-term complications such as post-phlebitic syndrome (40%)6and chronic thromboembolic
pul-monary hypertension (4%).7Although anticoagulant therapy
decreases the risk of recurrent thrombosis, the treatment also in-creases the risk of major hemorrhage. Before 1995 the approach was to image all patients with suspected DVT and to repeat tests 1 week later if results were negative.8,9This approach was
ineffi-cient, since only 10%–25% of patients with suspected DVT were found to actually have the disorder and results of serial tests were usually negative.9–12Over the last 10 years new strategies for
diag-nosing and treating suspected DVT have been introduced.
Diagnosis
Imaging tests
Compression ultrasonography is now the imaging test of choice to diagnose DVT. Lack of compressibility of a venous segment is the diagnostic criterion used, but the addition of Doppler
(in-cluding colour flow) can be useful to accurately identify vessels and to confirm the compressibility of a particular segment.
In many centres, ultrasound testing is limited to the proximal veins (from the common femoral vein caudally to the region of the calf veins where they join the popliteal vein), for which the sensitivity is 97%. For DVT in the calf veins the sensitivity is only 73%.13Since the distal calf is not scanned, it has been
demon-strated that the ultrasound should be repeated 1 week later (serial testing) if the result is negative to detect DVT extending into the proximal veins.9However, in symptomatic patients, only 20% of
thrombi detected are isolated to the calf, and only 20%–30% of these thrombi will eventually extend to the proximal venous sys-tem. (See Fig. 1 for the anatomy of the deep veins of the leg.) Therefore, routine serial testing is inefficient and inconvenient. Indeed, studies using the serial testing approach have shown that only 1%–2% of patients who have a negative initial ultra-sound result will be confirmed to have proximal DVT upon serial testing.13,14As a result, serial testing is not cost-effective.15,16 Clinical prediction rules
Although none of the symptoms or signs of DVT is diagnostic in isolation, it has been well established that a clinical prediction rule that takes into account signs, symptoms and risk factors can be accurately applied to categorize patients as having low, mod-erate or high probability of DVT (Table 1). Alternatively, the same rule can be used to categorize cases as “DVT likely” or “DVT un-likely.”17Over 14 studies have demonstrated the reproducibility
of this model.18Patients who are found to be at low pretest
prob-ability can have DVT safely excluded on the basis of a single neg-ative ultrasound result.10Thus, serial ultrasound testing can be
avoided in this subgroup of patients. The incorporation of plasma D-dimer testing into diagnostic algorithms can identify patients who do not require ultrasonography.17
D-dimer testing
D-dimer is a degradation product of a cross-linked fibrin blood clot. Levels of D-dimer are typically elevated in patients with acute venous thromboembolism, as well as in patients with a variety of nonthrombotic conditions (e.g., recent major surgery, hemorrhage, trauma, pregnancy or cancer).19
D-dimer assays are, in general, sensitive but nonspecific mark-ers of DVT. The value of the D-dimer assay resides with a neg-ative test result that suggests a lower likelihood of DVT, thus making it a good “rule out” test with the appropriate pretest
D O I: 10 .1 5 0 3 /c m aj .0 6 0 3 6 6
Dimitrios Scarvelis, Philip S. Wells
Diagnosis and treatment of deep-vein thrombosis
R
eview
Deep-vein thrombosis (DVT) is a common condition that can lead to complications such as postphlebitic syndrome, pul-monary embolism and death. The approach to the diagnosis of DVT has evolved over the years. Currently an algorithm strategy combining pretest probability, D-dimer testing and compres-sion ultrasound imaging allows for safe and convenient investi-gation of suspected lower-extremity thrombosis. Patients with low pretest probability and a negative D-dimer test result can have proximal DVT excluded without the need for diagnostic imaging. The mainstay of treatment of DVT is anticoagulation therapy, whereas interventions such as thrombolysis and place-ment of inferior vena cava filters are reserved for special situa-tions. The use of low-molecular-weight heparin allows for out-patient management of most out-patients with DVT. The duration of anticoagulation therapy depends on whether the primary event was idiopathic or secondary to a transient risk factor. More re-search is required to optimally define the factors that predict an increased risk of recurrent DVT to determine which patients can benefit from extended anticoagulant therapy.
Abstract
probability. If applied properly, incorporation of D-dimer testing into diagnostic algorithms simplifies the manage-ment of a patient presenting with suspected DVT.
Algorithm approach to DVT diagnosis
Patients with symptoms compatible with DVT should initially have a determination of pretest probability using an established prediction model (Table 1).17It is important that a history and
physical exam be done first. The model should be applied only if DVT remains a diagnostic possibility. After the clinical pretest probability is determined, a D-dimer test should be performed. In our centre, a score of less than 1 (unlikely DVT) by our current model, which incorporates previously documented DVT as a new variable, is sufficient to exclude DVT in patients with a neg-ative moderately sensitive D-dimer level without ultrasound im-aging.17No D-dimer assay should be used to exclude DVT in
pa-tients who have high pretest probability. Clinical assessment and D-dimer testing have the further advantage of enabling the management of patients with suspected DVT who present at times when radiographic imaging is not routinely available. Pa-tients in whom there is a moderate or high clinical suspicion of
DVT may receive an injection of low-molecular-weight (LMW) heparin in doses designed to treat acute DVT. Diagnostic imag-ing can then be arranged on a more elective basis the followimag-ing day. Since LMW heparin therapy is safe and effective for patients with proven DVT, it provides adequate protection for patients with suspected DVT.20,21For patients whose risk of DVT is low
(as determined either by means of a clinical diagnostic model or a sensitive D-dimer test), diagnostic imaging may be delayed for 12–24 hours without the need for anticoagulant coverage.10
Ac-cepted algorithms using our prediction model are outlined in Fig. 2. The clinical prediction rule was developed and validated predominantly in studies involving outpatients. Pregnant women were not included in these studies. Furthermore, the utility of the D-dimer test in patients admitted to hospital who often have other comorbidities (e.g., infection, postoperative symptoms) is lower since the D-dimer assay rarely yields nega-tive results. Finally, if DVT is not a diagnostic possibility, a D-dimer test should not be done, because a positive result may redirect a clinician away from investigating the true cause of the leg symptoms toward unnecessarily investigating for DVT.
The ideal strategy for diagnosing DVT in patients who have previously had DVT in the symptomatic leg is still a subject of debate. However, results of a random-ized trial demonstrated the safety of combining clinical probability, D-dimer and ultrasound imaging in these pa-tients.17The biggest concern with this
patient population is false-positive ultra-sound results. It is helpful to recognize that acute DVT is usually occlusive, not echogenic, and it tends to be continu-ous. If the ultrasound reveals throm-bosis that is echogenic, nonocclusive or discontinuous, then chronic DVT should be considered. Serial testing or venography can help to clarify the issue. Previous ultrasound results are helpful for comparison, when available. An in-crease in clot diameter by 4 mm sug-gests recurrence, as does extension.22
Most diagnostic and treatment stud-ies of DVT have excluded pregnant wo-men, and therefore it is difficult to formulate evidence-based recommenda-tions for this population. Although serial impedance plethysmography has been demonstrated to safely rule out DVT,23it
is not widely used. Results of a small pilot study suggest that a strategy involv-ing serial compression ultrasonography combined with a moderately sensitive D-dimer assay is effective in excluding DVT in pregnant women.24D-dimer levels are
often positive in the later stages of preg-nancy,25,26lowering the utility of this test
to rule out DVT. Research to develop al-gorithms to diagnose DVT in pregnant women is ongoing.
External iliac vein
Common femoral vein
Deep femoral vein
Superficial femoral vein
Popliteal vein
Anterior tibial veins
Peroneal veins
Posterior tibial veins
70%–80% of DVTs
involve the proximal veins on ultrasound, most commonly the popliteal vein and superficial femoral vein
20%–30% of DVTs are
isolated in veins of the calf: the anterior tibial, peroneal and
posterior tibial veins
Fig. 1: Diagram of leg veins (anterior view of right leg).
Li an n e Fr ie se n an d N ic h o la s W o o lr id g e
Treatment
The goal of the therapy for lower-extremity DVT is to prevent the extension of thrombus and pulmonary embolism in the short-term and to prevent recurrent events in the long-term. Based on extensive research evaluating the risk of recurrent DVT, guidelines have been established for the duration of an-ticoagulation therapy. LMW heparin therapy has changed the landscape of treatment of DVT by enabling home treatment and by providing an alternative long-term anticoagulant for people for whom warfarin is less effective or contraindicated. The following pertains to treatment of proximal lower-extremity DVT, since there is little evidence to formulate rec-ommendations for isolated DVT in calf veins.
Initial choice of anticoagulation
Initial therapy must involve therapeutic doses of either un-fractionated heparin or LMW heparin. Initial treatment with oral anticoagulant therapy alone is unacceptable.27The ease
of administration and efficacy of LMW heparin make this the preferred anticoagulant, whether given on an outpatient or an inpatient basis. In a meta-analysis comparing the effec-tiveness of LMW heparin at a fixed dose with unfractionated heparin at an adjusted dose, significantly fewer deaths, ma-jor hemorrhage and recurrent venous thromboembolism oc-curred with the LMW heparin.28Thus, the current standard
of care is to administer weight-adjusted LMW heparin once daily for 5–7 days as initial treatment. It remains unknown whether it is better to administer LMW heparin once or twice daily. The results of a meta-analysis suggested that hemor-rhage and recurrent venous thromboembolism were less likely to occur with twice daily dosing, but the 95% confi-dence interval on the odds ratio crossed 1.0.29Since LMW
parin is predominantly renally excreted, unfractionated he-parin should be used in patients with significant renal dysfunction. A newer agent is the synthetic pentasaccharide fondaparinux, which is at least as effective and safe as LMW heparin in the treatment of DVT.30Fondaparinux can be
con-sidered as an alternative agent for the treatment of DVT with the added benefit that, to date, heparin-induced thrombocy-topenia has not been reported with this agent. Unfortu-nately, the therapeutic dose formulation of fondaparinux (7.5 mg subcutaneously for most patients) currently is not available in Canada.
Early studies evaluating the outpatient treatment of pa-tients with DVT determined that this practice is safe and ef-fective in selected patients.31,32Subsequently, it was
demon-strated that a wide spectrum of patients (over 80% of those with DVT at our institution) could be treated as outpatients.33
This practice leads to an improved quality of life for the pa-tients and cost savings for the health care system.34Situations
that may necessitate inpatient treatment include comorbidi-ties requiring hospital management, renal failure, high bleed-ing risk (e.g., recent gastrointestinal hemorrhage), extensive DVT that leads to phlegmasia cerulea dolens, necessity for parenteral narcotics for pain control and an inability to have injections administered at home.
Long-term treatment
For the majority of patients with DVT, oral therapy with vitamin K antagonists (e.g., warfarin) is very effective for long-term pre-vention of recurrent thrombosis.35Although the initial treatment
of DVT is similar for most patients, the duration of long-term treatment varies depending on the perceived risk of recurrent DVT. The risk can be classified into the following 5 categories: • First proximal DVT occurs in the context of a transient risk
factor (e.g., surgery or trauma). In this situation, the risk of recurrence is very low and a limited duration of therapy (3 months) is adequate.36,37
• First DVT occurs in the context of active malignant disease, which is an ongoing risk factor. Patients with malignant disease have a higher incidence of recurrent thrombosis and bleeding complications while receiving oral anticoagulation therapy following a first thrombotic event.38,39This is likely
due to the prothrombotic state associated with cancer and to the difficulty of managing oral anticoagulant therapy with concomitant drugs, erratic oral intake and liver dysfunction. Researchers with the CLOT trial40have shown that
long-term anticoagulation therapy with LMW heparin is more ef-fective than warfarin at preventing recurrent venous throm-bosis without a statistically significant increase in bleeding risk. It is our practice to give all patients who have active ma-lignant disease LMW heparin for at least 6 months if there is adequate renal function. Not only will it lead to lower risks of recurrent thrombosis in many patients, but it facilitates the management of patients who need to undergo multiple procedures (e.g., biopsy, line insertion) and who have peri-odic thrombocytopenia due to chemotherapy. Since the risk of recurrence is high (2–3 fold higher among patients with cancer than among those without cancer),41treatment with
Table 1: Clinical model for predicting pretest probability of deep-vein thrombosis (DVT)*
Clinical characteristic† Score Active cancer (treatment ongoing, administered
within previous 6 mo or palliative)
1 Paralysis, paresis or recent plaster immobilization
of the lower extremities
1 Recently bedridden > 3 d or major surgery within
previous 12 wk requiring general or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Swelling of entire leg 1
Calf swelling > 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
Previously documented DVT 1
Alternative diagnosis at least as likely as DVT —2
*A score of 2 or higher indicates that the probability of DVT is “likely”; a score of less than 2 indicates that the probability is “unlikely.”
anticoagulation drugs is recommended as long as the can-cer is felt to be active. We wait 6 months after cure or com-plete remission before stopping therapy.
• First DVT occurs in the context of a thrombophilic defect. These defects include factor V Leiden, prothrombin gene mutation, deficiencies in protein C, protein S and anti-thrombin, increased factor VIII levels, hyperhomocysteine-mia and elevated antiphospholipid antibody levels. Many of these defects are associated with an increased risk of a first DVT. Patients with persistently elevated antiphospholipid antibody levels determined by either ELISA or clotting assays have a 2-fold higher relative risk of recurrence within 4 years after stopping anticoagulation therapy for a first DVT than those without this thrombophilia.37It has been reported that
patients with an elevated factor VIII level (above the 90th per-centile of normal) have a 2-year risk of recurrence of 37% after stopping anticoagulant agents, compared with 5% among those with normal levels.43However, this study
in-cluded lower risk calf vein thrombosis, which may explain the wide difference. In general, the risk of recurrence after a first idiopathic DVT is not influenced by the presence or ab-sence of most thrombophilic defects41and, with the
excep-tion of patients with elevated antiphospholipid antibody lev-els and combined or homozygous genetic defects,43we do
not routinely recommend prolonged anticoagulation therapy in these populations after a first idiopathic DVT.
• Recurrent DVT. After a second recurrence of DVT, the risk of further thromboembolic events following the discontin-uation of anticoagulation therapy is felt to be excessive if only 6 months of oral anticoagulation therapy is adminis-tered.44Therefore, we generally recommend that
anticoag-ulation therapy be continued in this situation. During yearly visits bleeding risk can be assessed, which will en-able a risk–benefit evaluation to determine if anticoagula-tion therapy should continue. However, no study has looked at the risk of recurrent DVT if both events occurred during a transient risk period. In this situation, a shorter duration of anticoagulation therapy may be adequate (3–6 months), but other factors may influence this decision. • First DVT occurs in the absence of temporary or identifiable
ongoing risk factors for thrombosis (idiopathic). Six months is considered a minimum duration for anticoagulation ther-apy in these patients, while continuing for longer is effective in preventing thrombosis. However, the risk of recurrent ve-nous thromboembolism in the first year after stopping anti-coagulation therapy is about 10%, regardless of when the therapy is stopped after 6 months.45When considering
pro-longing anticoagulation therapy after 6 months, the risks of bleeding with long-term anticoagulation therapy must be in-dividualized and weighed against the potential benefits of preventing recurrence of thrombosis.
In addition to the thrombophilic defects described
previ-Determination of pretest probability of DVT DVT unlikely (probability score ≤1) DVT likely (probability score > 1)
D-dimer test D-dimer test
No DVT Ultrasound*
*Imaging done from proximal veins to calf trifurcation.
No DVT Ultrasound* No DVT Treat with anticoagulation therapy Ultrasound* Repeat ultrasound* in 1 wk No DVT Treat with anticoagulation therapy + + + + + + — — — — — —
ously, 2 factors have been shown to increase the risk of recur-rence after stopping anticoagulation therapy. Residual thrombosis (seen on a follow-up ultrasound scan 3 months after an initial event) increases the risk of recurrence (odds ra-tio 2.4).46One-third of the recurrences occur in the initially
unaffected leg, which suggests that residual DVT is a marker of systemic hypercoaguability. In one study, elevated D-dimer levels 1 month after stopping anticoagulation therapy were associated with an elevated risk of recurrent thrombosis in all but cancer-related thrombosis.47However, it is unclear how
to incorporate these factors into clinical decision-making. In an attempt to provide clinical guidelines, our Venous Throm-boembolism Clinical Trials group (VECTOR) is conducting a study designed to create a decision rule on recurrence risk. Intensity of anticoagulation therapy
The standard intensity of oral anticoagulation therapy is an in-ternational normalized ratio (INR) of 2 to 3. In patients who have antiphospholipid antibody-related thrombosis, it has long been felt that higher intensity anticoagulation therapy is needed to prevent recurrence.48However, results of 2
random-ized controlled trials showed that standard anticoagulation therapy is as effective as high-intensity treatment, even in this subgroup of patients.49,50Therefore, high-intensity
anticoagu-lation therapy is not recommended in any patient with DVT. Maintaining good INR control will decrease the risk of post-phlebitic syndrome.51There has also been debate on the
use-fulness of long-term low-intensity anticoagulation therapy (INR 1.5–1.9) to prevent recurrent thrombosis while reducing the risk of bleeding. A large randomized trial has shown that low-intensity anticoagulation therapy is less effective than standard anticoagulation therapy at preventing recurrent thrombosis and does not lower the risk of bleeding.52
There-fore, low-intensity therapy is not recommended. Upper-extremity DVTs
Upper-extremity DVTs can be subdivided into catheter- and non-catheter-related thrombosis. There is a risk of pulmonary em-bolism with this condition, and therefore treatment with antico-agulation therapy is generally recommended. Initial treatment with thrombolytic therapy for acute upper-extremity DVT has been used with some success, but no randomized controlled tri-als comparing thrombolytic therapy with anticoagulation ther-apy alone have been performed. A more detailed discussion of upper-extremity DVT is beyond the scope of this article, and we would refer the reader to a review addressing this topic.53 Special patient populations
The treatment of DVT during pregnancy deserves special mention, since oral anticoagulation therapy is generally avoided during pregnancy because of the teratogenic effects in the first trimester and the risk of fetal intracranial bleeding in the third trimester. LMW heparin is the treatment of choice for DVT during pregnancy. If acute DVT occurs near term, in-terrupting anticoagulation therapy may be hazardous because
of the risk of pulmonary embolism. In this situation, place-ment of a retrievable inferior vena cava filter must be consid-ered. However, there is no consensus as to what the appropri-ate dose should be and whether anti-Xa levels need to be monitored. This topic is well discussed in a recent review.54
For obese patients with DVT, results of a registry study suggest that they have similar outcomes as nonobese patients with DVT.55The dose of LMW heparin does not need to be
capped, and monitoring is not required, except perhaps in people who are morbidly obese, since fewer data are available for these patients.56,57
Other interventions
Although anticoagulation therapy is the mainstay of treatment of DVT, thrombolysis and placement of an inferior vena cava fil-ter are 2 infil-terventions that deserve mention. The addition of sys-temic thrombolysis to standard anticoagulation therapy leads to earlier patency of an occluded vein; however, it does not affect the rate of pulmonary embolism. There is a definite increase in the risk of major hemorrhage, including intracranial hemor-rhage, with thrombolysis. Catheter-directed thrombolysis has also been associated with increased risk of bleeding complica-tions. It is unclear whether the earlier recanalization seen with thrombolysis translates into lower rates of postthrombotic syn-drome over the long term.58,59Thrombolysis is not generally
rec-ommended except in the case of massive DVT, which leads to phlegmasia cerulean dolens and threatened limb loss.
Placement of an inferior vena cava filter in addition to antico-agulation therapy has not been found to prolong survival among patients with DVT. While preventing pulmonary embolism, in-sertion of a filter increases the risk of recurrent DVT.60,61A
re-trievable filter is indicated when there is a contraindication to an-ticoagulation therapy (recent hemorrhage, impending surgery) in patients with newly diagnosed proximal DVT. It remains to be determined if a retrievable filter in patients at higher risk of death (e.g., limited cardiopulmonary reserve) will lead to a reduction in pulmonary embolism-related death.
Postphlebitic syndrome is a frequent complication of DVT and a major public health issue that has been under-researched. It is unclear who is at highest risk and how best to prevent and treat this complication. Some data suggest a potential benefit from the use of graduated compression stockings, and our VECTOR group is currently investigating this issue in a randomized trial. Postphlebitic syndrome is well reviewed in a recent publication.7
This article has been peer reviewed.
From the Departments of Medicine (Scarvelis, Wells) and of Community Medicine and Epidemiology (Wells), the Division of Hematology (Scarvelis, Wells), and the Ottawa Health Research Institute (Scarvelis, Wells), Univer-sity of Ottawa, Ottawa, Ont.
Competing interests: None declared for Dimitrios Scarvelis. Philip Wells has
received honoraria for speaker fees from Leo Pharma, Sanofi-Aventis and AstraZeneca, and sits on a steering committee for a study of a new anticoagu-lant sponsored by Bayer.
Contributors: Both authors contributed substantially to the manuscript,
in-cluding drafting the article and revising it critically for important intellectual content, and approved the submitted version.
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Correspondence to: Dr. Dimitrios Scarvelis, Division of Hematology,
The Ottawa Hospital, Rm. 462, 737 Parkdale Ave., Ottawa ON K1Y 1J8; fax 613 761-4840; dscarvelis@ottawahospital.on.ca
